Breast Diseases

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[edit] Breast Diseases

Barbara A. Ward

Michael Reiss

Breast cancer afflicts one of every eight to nine American women, an alarming statistic. Among women in the United States, it is the most often diagnosed malignancy and follows only lung cancer as the leading cause of cancer death. Given the high incidence of this disease, a working knowledge of breast anatomy, diagnostic procedures, and breast cancer treatment is essential. Moreover, issues of breast cancer risk assessment and prevention are becoming increasingly relevant to the primary care physician. In addition, benign conditions that affect the breast are quite common and often perplexing. This chapter outlines the basic steps regarding breast evaluation and describes the options in the management of breast masses and breast cancer.

[edit] OVERVIEW

[edit] Common Benign Conditions

Fibrocystic disease, or mastopathy, refers to breast lumpiness accompanied by pain and tenderness that is most severe in the premenstrual phase of the cycle. Although the term fibrocystic is nonspecific, most physicians can identify the clinical picture it represents. It is most accurate to describe fibrocystic changes based on the specific microscopic entity involved, including fibroadenomas, macrocysts, periductal mastitis, papillomatosis, apocrine metaplasia, sclerosing adenosis, and hyperplastic lesions of the duct and lobule.

Fibroadenomas typically present during the second and third decades but may be found at any age. Excision is generally advised because the lesions may continue to grow and may be confused with cystosarcoma phyllodes or a carcinoma. Cysts tend to appear suddenly and are much more common in the premenopausal age group. They are often tender and may be aspirated to relieve symptoms and to confirm the diagnosis. Although ultrasound is helpful in differentiating a cyst from a solid mass, needle aspiration with complete resolution of a palpable mass is the gold standard. Macrocysts generally diminish after menopause but may persist in the patient receiving hormonal replacement therapy (HRT). Periductal mastitis is a chronic condition characterized by repetitive infections that are difficult to treat. Excision of the involved duct system is the recommended treatment. Although antibiotics may temper the inflammation, they are not curative, because nests of purulent fluid remain in undrained recesses.

[edit] Breast Cancer

In 2000, an estimated 182,800 new breast cancers will be diagnosed in the United States, and an estimated 40,800 women will die from this disease. Over her lifetime an American woman has a 12.5% risk of developing breast cancer and a 3.5% risk of dying from it. The incidence and risk of developing breast cancer increase with age, and the majority of cases occur in postmenopausal women (Fig. 43-1). Nonetheless, even though 80% of women who die are over 55, breast cancer is the second most common cause of death in younger women between ages 35 and 55.

Figure 43-1 Age-specific breast cancer incidence in women (SEER Program), 1991 to 1995. Rates are per 100,000 women and are age adjusted to standard world population. (From Ries LAG, Kosary CL, Hankey BF, et al, editors: SEER cancer statistics review, 1973-1995, Bethesda, Md, 1998, National Cancer Institute.)

Breast cancer incidence in females increased from 88.6 per 100,000 in the early 1970s to 109.8 in 1990. Since 1990 the incidence has remained stable. Changes in lifestyle may have contributed to the increased incidence of breast cancer in the 1970s and 1980s. Earlier menarche, delayed childbearing, and pharmacologic uses of estrogens have increased the total period in a woman's life that her breast epithelium is exposed to and stimulated by estrogens and progestins. Changes in nutrition and other environmental factors yet to be identified may have also played a role. For example, population studies have suggested a direct correlation between dietary fat consumption and breast cancer incidence around the world, although case-controlled studies have been unable to confirm this association. Furthermore, the evidence that modifying dietary fat intake reduces breast cancer risk remains inconclusive. The relationship between alcohol consumption and breast cancer risk remains equally controversial.

The relative incidence of in situ and lymph node–negative invasive cancer increased rapidly from 1982 through 1987 and has since leveled off, whereas the relative incidence of lymph node–positive invasive breast cancer has decreased since 1987. These recent fluctuations in stage at diagnosis of breast cancer likely reflect the introduction and large-scale application of screening mammography since the early 1980s.

Between 1973 and 1990 the age-adjusted breast cancer mortality rate for U.S. women rose steadily at a rate of approximately 0.2% per year. Since 1990, however, breast cancer mortality has greatly decreased, by approximately 2% per year, in all age groups. Statistical modeling indicates that this recent drop in breast cancer mortality is too rapid to be explained solely by the increased use of mammography but almost certainly reflects the impact of improvements in systemic adjuvant therapy (see later discussion).

[edit] PATHOPHYSIOLOGY

[edit] Growth and Development

Anatomically the breast is a hormonally sensitive gland that develops and regresses with each menstrual cycle and with age. The adult breast is composed of epithelial and stromal elements. The stroma contains adipose tissue and fibrous connective tissue, both of which predominate in the nonlactating breast (Fig. 43-2). The epithelial component consists of 15 to 20 branching ducts that originate from the nipple and terminate in lobules with clusters of small acini. During pregnancy this glandular component increases so that the breast is composed mainly of epithelial elements, which persist throughout lactation. After lactation, breasts undergo a process of involution and return almost completely to the virginal state. After menopause, stromal adipose tissue increases, whereas all other stromal and epithelial elements diminish in size.

Figure 43-2 Anatomy of female breast. (Redrawn from NIH Pub No 91-1556, October 1990.)

Variations in breast anatomy are common. The majority of women have a slight asymmetry to their external breast appearance; this difference may be marked in some individuals. Accessory nipples, which are apparent at birth, are generally but not necessarily bilateral and are found along the midclavicular line. Breast tissue extending to the axilla may not be clinically apparent until pregnancy occurs and the area becomes swollen and tender. If symptoms are marked, the areas may be excised postpartum in anticipation of future pregnancies. The syndromes of virginal breast hypertrophy and Poland's syndrome, the congenital absence of the breast, nipple, and pectoralis muscles, are rare. Male gynecomastia is usually seen in the prepubertal male and is generally transient (see Chapter 7 ). Surgery can be performed if the patient finds significant enlargement embarrassing or painful. Gynecomastia is also common in the aging male and is exacerbated by certain medications or hepatic dysfunction. It is characterized by classic findings on mammography.

[edit] Histopathology of Breast Cancer

Most invasive breast cancers are adenocarcinomas, which can be quite heterogenous in histologic appearance and can be classified into several different subtypes with varying prognostic implications. Approximately 80% of adenocarcinomas are of the infiltrating (i.e., invasive) ductal type. Although they vary in degree of differentiation, infiltrating ductal carcinomas have a common natural history and metastasize predominantly to the skeleton, lungs, liver, and brain. Infiltrating lobular carcinomas account for approximately 10% of adenocarcinomas. Although the overall prognosis is similar to that for invasive ductal carcinoma, invasive lobular carcinomas tend to spread to the meninges rather than the brain parenchyma; to serosal surfaces such as the pleura, the peritoneum, and the surface of the ovaries; and to mediastinal and retroperitoneal lymph nodes. Less common variants of breast carcinoma, including tubular, medullary, mucinous, and papillary carcinomas, are well differentiated and carry a relatively favorable prognosis.

Noninvasive cancer that is confined to the ducts without penetration of the basement membrane is termed ductal carcinoma in situ (DCIS), or intraductal carcinoma. DCIS is the earliest form of breast cancer and is often detected only by screening mammography. In contrast, lobular carcinoma in situ (LCIS) is not a malignant lesion but a histopathologic entity that confers an increased risk for developing invasive breast cancer in either the ipsilateral or the contralateral breast.

[edit] EVALUATION OF BREAST MASS

The differential diagnosis of a breast mass includes primary breast cancer; fibrocystic changes, cyst, fibroadenoma, or an associated benign mass; abscess or mastitis; phyllodes tumor; lipoma; fat necrosis; duct ectasia; sarcoma; sarcoidosis; lymphoma; metastatic cancer; skin conditions such as sebaceous cysts; costochondritis; superficial thrombophlebitis or Mondor's disease; and tumors of the chest wall. Certain lesions are most common in different age groups (Table 43-1). A new breast mass in a woman older than 50 years should be considered cancerous until proved otherwise. In contrast, cancer is uncommon in women under age 35 and highly uncommon in those under 25. The history and physical examination generally narrow down the differential diagnosis, but ultimately, pathologic examination is required for the definitive diagnosis.

Table 43-1 Diagnostic Approaches to Palpable Breast Masses

[edit] Patient History

The patient's age is critical in the assessment of new breast masses and helps to categorize risk. A family history of breast cancer should be noted, but because the majority of women who develop breast cancer do not have a family history of this disease, a negative family history cannot be assumed to be protective. A complete history should include assessment of duration, growth pattern, relation to menstrual cycle, spontaneous nipple discharge, pain, and tenderness. Cumulative estrogen exposure should be estimated by noting age at menarche and menopause, use of oral contraceptives and HRT, number of pregnancies and live births, and duration of breast-feeding. Previous breast biopsies, timing of mammograms, and previous ultrasounds need to be ascertained as well.

Past medical history may be relevant. A previous diagnosis of colon or endometrial cancer places the patient in a higher risk category for breast cancer. Other diseases that may involve the breast include sarcoidosis, lymphoma, and metastatic melanoma. Past surgery, such as oophorectomy, is important, as are certain medications, such as antidepressants, which may be associated with nipple discharge.

Nipple discharge is a fairly common complaint and is generally related to a benign condition. Concern increases if the discharge is unilateral, spontaneous, and bloody; emanates from one duct system alone; or occurs in a postmenopausal patient. Even with these concerns, the most common source for nipple discharge is an intraductal papilloma, a benign condition treated by excision alone. Cytologic examination of the nipple discharge may reveal malignant cells, but a negative cytologic examination does not confirm benignity. Mammography should be performed to identify any occult mass or source for the discharge, followed by nipple exploration and duct excision. Some surgeons find ductograms helpful in delineating the anatomy of the duct system and intraluminal defects.

[edit] Physical Examination

The breast is a pear-shaped structure, with the tail of Spence angled toward the axilla. Most active breast tissue is located in the upper outer quadrant, where most benign and malignant masses occur. Glandular breast tissue resembles a bunch of grapes, with the grapes representing the lobules and the branches coalescing as the ducts at the nipple. The outer breast tissue has a normal ``lumpy consistency, similar to the outer periphery of a bunch of grapes. A true mass, however, is distinct from the bunch and possesses three dimensions. Firm masses with irregular borders are suspicious for malignancy. Normal ridges of tissue are palpable medially, where breast tissue may be accentuated by the underlying rib structure; inferiorly, where a ptotic breast forms an inframammary fold; and centrally around the edge of the nipple, where a ``rim effect may be felt. These variations should be bilateral unless surgery has altered breast symmetry.

Because of normal cyclic changes of the breast throughout menses, the best time for examination is generally 10 to 14 days after menstruation. Immediately before the onset of menses, the breasts are most engorged and tender; cysts may be largest at this time and recede after menstruation. Pregnancy produces a more sustained engorgement, which is ultimately relieved with lactation. A lumpy texture results as milk is temporarily sequestered in lobules. A persistent, new mass that presents during lactation should be evaluated, however, beginning with an ultrasound. Solid masses should be biopsied, although this procedure may require that breast feeding be interrupted. As the patient approaches menopause, the breast may be affected by fluctuations in hormonal levels, resulting in increased tenderness and enlarging cysts. Because the aging breast is at increased risk for cancer, these new masses should be evaluated, aspirated if appropriate, and followed. After menopause, cysts are uncommon unless the patient is maintained on HRT. The difficulties of follow-up in the cystic breast must then be weighed against the potential benefits of HRT for a given patient.

The examination should begin with the patient disrobed in the upright position. The examiner checks for symmetry, skin thickening, nipple changes, and skin dimpling, particularly with the patient's arms raised. One breast may be slightly larger than the other, and most patients will confirm that this condition has been longstanding. The patient is then asked to lie down and raise her arm laterally above her head as each breast is examined. This maneuver is most helpful in women with large breasts. In a woman with smaller breasts, the skin may be too taut with the arm raised, and examination is easier with the patient's arm at her side. If a patient has noted a mass, she should point it out. The examination should then proceed, covering all four quadrants of the breast in a uniform, thorough manner. If a patient is not familiar with breast self-examination (BSE), this is a good time to repeat these steps with her hand (Fig. 43-3). Although some women find BSE awkward, it is a shared responsibility, and most patients improve with encouragement, coaching, and instructional materials.

Figure 43-3 Breast self-examination (BSE). (Redrawn from NIH Pub No 91-1556, October 1990.)

The physical examination proceeds with an examination of the supraclavicular and axillary lymph nodes. Small axillary lymph nodes are typically felt in a thin person; however, a palpable node becomes more relevant when a coincident breast mass is also palpated. The axillary node is best examined with the patient in the upright position and the arm relaxed, resting on the examiner's forearm. The node examination may be slightly uncomfortable because this is often a tender area in a totally benign axilla. Palpation for axillary nodes from the posterior may make the axillary examination less uncomfortable for the patient. In the unfortunate patient with a highly suspicious mass, the physical examination should include a search for metastatic disease, such as hepatomegaly and points of bony tenderness.

When a breast mass is present, its physical characteristics may be helpful in determining a diagnosis. A suspicious mass is three dimensional and firm with indistinct margins. Fibroadenomas classically are slippery, smooth, and easily movable within the breast. Although cysts are also smooth, they are not significantly mobile. Cysts may feel ballotable, as a water-filled balloon, or hard when they are tense with fluid. Although these characteristics are ``classic, a diagnosis should not be made exclusively based on clinical characteristics. Every physician has been fooled by a cancer that presents as a ``nonsuspicious smooth mass. Given this dilemma, it is generally safe to recommend a biopsy, which provides a definitive microscopic diagnosis.

Given the high frequency of breast cancer, every woman should be instructed regarding the three tools to early diagnosis: BSE, mammography, and periodic examination by a health care professional. Because mammography is least helpful in the dense, lumpy breast, physical examination is an essential tool.

[edit] Diagnostic Procedures

Screening mammography has led to the detection of breast cancers at earlier stages than those detected without screening. The American Cancer Society (ACS) recommends that mammograms be performed every year to every other year between ages 40 and 50 and every year after age 50. The benefit of screening mammography is greatest in women ages 50 to 69; several studies have demonstrated a reduction of breast cancer mortality in this population. Currently the value of screening mammography in women ages 40 to 49 remains controversial. Results from the Canadian National Breast Screening Study showed no survival benefit from screening in this age group after 5 to 7 years. However, these results have been refuted by other studies, leading the U.S. National Cancer Institute (NCI) to suggest screening in this age group. Most physicians believe that it is reasonable to continue to follow the recognized guidelines until sufficient evidence results in a change. Furthermore, if a patient has a mother or sister with premenopausal breast cancer, the screening recommendations are moved up by 10 years before the age at cancer diagnosis in the first-degree relative; at a minimum, yearly mammograms are performed after age 40. Issues about screening should not be confused with the importance of mammography in the workup of symptomatic patients.

When mammographic abnormalities are seen on a screening study, patients may be asked to return for magnification or compression views to clarify a problem. With a cancer, compression may accentuate the finding, whereas in normal dense parenchyma the abnormality is dispersed. Macrocalcifications are not related to cancers, but clustered microcalcifications, which are laid down within a lobule or duct, can herald an early malignant lesion. An increase in the number and density of microcalcifications is a common reason for biopsy, even though only 25% to 30% of biopsies performed for microcalcifications yield a diagnosis of cancer. If possible, it is often reassuring to show patients their mammographic abnormality. This approach gives them a real estimate of the minute size of the lesion being addressed.

Biopsies can be performed using several different methods. If a mass is palpable, a needle biopsy may be performed in the surgeon's office. This procedure is generally reserved for a mass that is suspicious for cancer. A negative result, in this instance, would still require an excisional biopsy to remove the entire mass. Excisional biopsies are usually performed in the outpatient setting, with treatment decisions based on the final pathologic finding.

New techniques have been developed for nonpalpable masses seen only by mammography. Biopsy using needle localization requires placement of a barbed wire or contrast dye in proximity to the lesion, followed by two mammographic views demonstrating the relationship of the lesion to the wire or contrast dye. The surgeon then removes the designated tissue surrounding the wire. Because the surgeon usually cannot see the ``lesion even after making the incision, the specimen is subjected to radiography to confirm removal of the abnormality. Stereotactic biopsy is a relatively new technique that uses a specialized mammographic machine to localize precisely the area of breast abnormality. Approximately five to eight large-core needle biopsies are taken, which provide samples of tissue for pathologic examination. The technique is valuable in diagnosing a finding highly suspicious for cancer on mammography as well as lesions thought to be consistent with a fibroadenoma or intramammary lymph node. A core biopsy that confirms a benign lesion (e.g., fibroadenoma) negates the need for an open biopsy. If the biopsy yields only normal breast tissue, however, an open biopsy is recommended if the lesion is highly suspicious mammographically for cancer; alternatively, a 6-month follow-up mammogram may be recommended for less suspicious lesions. The advanced breast biopsy instrumentation (ABBI) technique combines stereotactic localization with an excisional biopsy device that removes a 5-mm to 20-mm core of breast tissue. In many diagnostic centers, stereotactic or ABBI biopsies have largely replaced the open biopsy method with needle localization.

The role of magnetic resonance imaging (MRI), Doppler ultrasound, Sestamibi scans, and other modalities in the diagnosis of breast cancer are currently being investigated. These techniques may differentiate malignancy from benign disease based on differences in enhancement and vascular signals. More proof of clinical efficacy is needed before these techniques become part of the routine evaluation of breast disorders. Currently they are used to assist with the interpretation of complex mammograms and to differentiate between malignant changes and scar tissue.

[edit] BREAST CANCER MANAGEMENT

[edit] Staging

The purpose of staging is to provide an estimate of tumor burden, which is the most important predictor of prognosis (Table 43-2). Patients with DCIS (Stage 0) have the best outcome, with nearly universal cure; patients with distant metastases (stage IV) have the worst prognosis, with essentially no chance for cure. Women with early-stage or localized breast cancer are at varying risk of developing metastatic disease, depending primarily on involvement of axillary lymph nodes with metastatic cancer. Thus nodal status is most often used to discriminate between stage I (lymph node–negative) and stage II (lymph node–positive) early-stage breast cancer. Women with locally advanced (stage III) breast cancer require an aggressive combined-modality approach to therapy because of an exceedingly high risk of systemic disease.

Table 43-2 Incidence and Outcome of Breast Cancer by Stage

✢Ductal carcinoma in situ (DCIS).

Sentinel lymph node identification is a novel technique for staging of regional lymph nodes. Using a radioisotope (technetium 99) or a vital dye (isosulphan blue), the flow of lymph from a breast cancer to the lymph node basin can be mapped. A complete axillary lymph node dissection may be avoided when the sentinel node is identified and histologically free of tumor.

[edit] Prognostic Indicators

The prognosis of cancer is directly related to the presence of micrometastases and their propensity to develop into clinically important metastases. In the absence of direct assays for the presence of subclinical metastases, other factors are used to predict which patients with early-stage breast cancer are more or less likely to develop recurrent disease. This information is particularly useful for patients with stage I disease, for whom the relatively low risk of recurrence must be balanced against inherent risks of systemic adjuvant therapy.

The two most important prognostic factors are (1) the presence or absence of metastases in regional lymph nodes and (2) the expression of hormone receptors in the primary tumor (Table 43-3). Patients without lymph node metastases (stage I) have a significantly lower risk of developing and dying from recurrent breast cancer than patients with nodal metastases detected at diagnosis (stage II). Furthermore, the risk of recurrence and mortality increases with the number of lymph nodes containing metastatic deposits. Tumors that express either estrogen receptors (ER-positive tumors) or progesterone receptors (PR-positive tumors) have an improved prognosis and are more likely to benefit from adjuvant hormonal therapy and to respond to endocrine therapy for metastatic disease.

Table 43-3 Prognostic Indicators of Early-stage Breast Cancer

✢ER, Estrogen receptor; PR, progesterone receptor.

In patients with lymph node–negative disease, indices such as the size of the primary tumor, ER and PR expression, proliferative rate, and deoxyribonucleic acid (DNA) content are important independent determinants of outcome and are helpful in making recommendations for adjuvant systemic therapy. Generally, patients with tumors less than 1 cm in diameter have an extremely low risk of recurrence and do not require adjuvant therapy. Laboratory analysis by flow cytometry detects tumors that contain a high fraction of cells in S phase and therefore are rapidly proliferating. Such tumors carry a worse prognosis than those that divide more slowly (low S-phase fraction).

[edit] Ductal Carcinoma In Situ

The use of mammography has led to a dramatic proportional increase in the number of women diagnosed with DCIS over the past 15 years. These lesions are most often identified on mammograms as clustered microcalcifications with or without a palpable mass. Although these lesions are traditionally treated by mastectomy, recent data support the efficacy of lumpectomy and radiation for women with localized DCIS. Treatment decisions are tailored to the clinical scenario. For example, when a minute focus of DCIS is discovered, lumpectomy alone may be used. Alternatively, when mammography demonstrates extensive microcalcifications involving a large segment of the breast, simple mastectomy is the treatment of choice. Generally, axillary lymph node dissection is not required in the treatment of DCIS. Exceptions to this approach include (1) involvement of a large area of breast in which an area of microinvasion may be missed on histology and (2) the diagnosis of comedo carcinoma, which is known to have a low but recognized risk of lymph node metastases. After excision and radiation therapy, treatment of DCIS with the antiestrogen tamoxifen may further reduce the incidence of local recurrence and second primary cancers.

[edit] Early-Stage Invasive Disease

[edit] Local Treatment.

The standard options for the primary treatment of invasive breast cancer are wide local excision (lumpectomy) and axillary lymph node dissection, combined with radiation therapy, or modified radical mastectomy, which includes a lymph node dissection. Multiple studies have shown that the survival of women treated with either of these two approaches is identical. Survival rates ultimately reflect spread to distant organ sites, which is not affected by type of treatment.

The primary goal of lumpectomy is to excise the tumor with negative microscopic margins. If the initial biopsy demonstrates that the cancer extends beyond the margins of resection, a reexcision is performed at the time of lymph node dissection. Radiation therapy is given over 6 weeks in divided doses, sometimes supplemented by a ``boost to the lumpectomy site with x-rays, electron beam, or brachytherapy. The patient is followed by interval mammography of the treated breast and the contralateral breast. Approximately 10% to 15% of women will develop a local recurrence after lumpectomy and radiation therapy and generally are treated by mastectomy.

Indications for modified radical mastectomy, which spares the chest wall muscles, include large tumors in a relatively small breast. If a lumpectomy would result in a distorted appearance or positive margins, mastectomy is also preferable. Traditionally, subareolar lesions were treated by mastectomy, but many patients prefer lumpectomy, even if this results in a breast without a nipple, to breast reconstruction. These options must be discussed with the patient. Patients with multifocal disease, a history of prior chest irradiation, collagen vascular disease, or inability to travel for radiation treatments are better served with mastectomy.

Breast reconstruction can be accomplished at the time of the primary treatment or after chemotherapy. If the physician and patient are concerned about the apparent aggressiveness of a tumor with suspicious palpable axillary nodes at presentation, reconstruction should be delayed because wound healing or implant infections could prolong the postoperative convalescent period and delay further treatment. Other than this consideration, reconstruction at mastectomy has multiple benefits, including a single operative procedure and hospitalization and a superior cosmetic result. The choice of reconstruction is decided by the patient and plastic surgeon, based on body habitus and personal choice. Common options currently include saline implant placement or myocutaneous flaps that use the rectus abdominis or latissimus dorsi muscles.

[edit] Adjuvant Therapy.

Adjuvant systemic therapy is administered to patients with early-stage invasive breast cancer when a strong potential exists for relapse from subclinical micrometastases. Because approximately 60% to 70% of patients with node-positive and 30% of patients with node-negative malignancies eventually develop metastatic breast cancer, a large cohort of women may benefit from adjuvant chemotherapy. All women who harbor micrometastatic disease likely derive some benefit from adjuvant therapy even if micrometastases are not eradicated, because the treatment delays the onset of metastatic disease.

[edit] Polychemotherapy.

An analysis of almost 50 randomized clinical trials of systemic adjuvant chemotherapy involving about 18,000 women worldwide has provided clear evidence that adjuvant combination chemotherapy (polychemotherapy) significantly improves the survival of women with early-stage breast cancer (Table 43-4). Overall, adjuvant chemotherapy reduces the risk of recurrence (i.e., metastatic disease) by 35% in women under 50 and by 20% in women over 50. This has resulted in significant improvements in overall survival at 10 years in all age groups, although the impact of chemotherapy is clearly greatest in younger women. Adjuvant chemotherapy also has been shown to improve the outcome of women regardless of involvement of axillary lymph nodes; however, the magnitude of this benefit is generally greater for women with node-positive than those with node-negative breast cancer.

Table 43-4 Impact of Adjuvant Polychemotherapy in Early-stage Breast Cancer at 10 Years

Combination chemotherapy regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) administered for 6 months or doxorubicin (Adriamycin) administered for 3 months are often recommended for women with a significant risk of recurrent disease. The addition of paclitaxel (Taxol) may further improve the outcome of women with node-positive disease. High-dose chemotherapy with autologous or peripheral blood stem cell support is under active investigation for women who are at extremely high risk of recurrence (i.e., those with four or more positive lymph nodes). Using this approach, 65% of patients with 10 or more involved lymph nodes have remained free of disease after 10 years, compared with only 30% of historic controls treated with conventional chemotherapy. Recently a regimen of sequential administration of dose-intense Adriamycin, Taxol, and cyclophosphamide (ATC regimen) that does not require stem cell support has similar efficacy with greatly reduced toxicity and cost.

[edit] Endocrine Therapy.

Oophorectomy, which removes the principal source of estrogen, is a highly effective way to improve survival of premenopausal women with early-stage breast cancer. Similarly, adjuvant therapy with the antiestrogen tamoxifen prolongs disease-free and overall survival. Based on a meta-analysis of 55 randomized trials involving 37,000 women, adjuvant tamoxifen administered for at least 5 years reduces the risk of recurrence by almost 50% and the risk of death by more than 25% (Table 43-5). The risk of developing a contralateral second primary breast cancer is also reduced by 50%. All women diagnosed with ER-positive or PR-positive cancer derive the same proportional benefit from adjuvant tamoxifen, regardless of their age and involvement of axillary lymph nodes. The benefits of adjuvant chemotherapy and tamoxifen appear to be independent and additive. Thus, whenever chemotherapy is indicated, patients derive significant incremental benefit from the addition of tamoxifen if the tumor is ER or PR positive. Furthermore, because tamoxifen displays estrogen agonist properties in the cardiovascular and skeletal systems, the risk of death from cardiovascular disease may be reduced, and loss of bone mineral density is slowed. Table 43-6 summarizes current recommendations for adjuvant systemic therapy in breast cancer.

Table 43-5 Impact of 5 Years of Adjuvant Tamoxifen in Early-stage Breast Cancer at 10 Years✢

✢Excluding estrogen receptor–negative cancers.

Table 43-6 Current Recommendations for Adjuvant Systemic Therapy in Breast Cancer

[edit] Toxicity.

The benefits of adjuvant endocrine therapy and chemotherapy must be weighed against the risks of immediate and delayed toxicity. Table 43-7 lists the most common acute and long-term side effects associated with adjuvant endocrine therapy and chemotherapy. Leukopenia occurs more frequently with doxorubicin-containing regimens, but life-threatening infections are rare. Fatigue occurs in more than 50% of patients, regardless of the regimen. Marked alopecia is rare with CMF but occurs in virtually 100% of patients receiving doxorubicin. Weight gain of 4 to 5 kg within 1 year is typical. Premature menopause occurs in 95% of patients over age 40 who receive CMF-based adjuvant chemotherapy regimens but is significantly less frequent after the shorter doxorubicin regimen. Early menopause is associated with all the symptoms of physiologic menopause, including hot flashes, atrophic vaginitis, decreased libido, infertility, osteoporosis, and increased risk of cardiovascular disease. Periodic measurements of bone mineral density should be performed and treatment of osteopenia and/or osteoporosis with calcium supplementation, exercise, and biphosphonates may be required.

Table 43-7 Toxicity Associated with Adjuvant Systemic Therapy

Tamoxifen is well tolerated in most patients and is associated with few side effects. The major toxic effects occur in premenopausal patients and are limited to hot flashes (55%) and irregular menses (40% to 60%). One fourth of both premenopausal and postmenopausal women experience increased vaginal discharge. Phlebitis and early-stage endometrial carcinoma occur infrequently. Tamoxifen has additional long-term side effects that are beneficial rather than detrimental, such as improvement in bone mineral density and serum lipid profile and a reduction in ischemic heart disease. Because tamoxifen and raloxifene have similar antiresorptive properties, women being treated with adjuvant tamoxifen are unlikely to benefit from the addition of raloxifene.

[edit] Follow-up.

All breast cancer patients should undergo lifetime surveillance for second primary breast cancers, as well as for recurrent disease. Although the majority of metastases occur within 5 years of diagnosis, relapses may be delayed for as long as two or three decades. Furthermore, these women have a lifelong risk of developing secondary breast cancers of approximately ½% to 1% per year. Follow-up evaluations should include a history and complete physical examination, complete blood count (CBC), liver function tests, and yearly mammography. Patients are typically seen every 3 to 4 months for the first 3 years, twice a year for the next 2 years, and yearly thereafter. No definitive evidence shows that early detection of asymptomatic metastases improves survival or palliation. Thus, although symptoms should be investigated to rule out metastatic disease, routine screening of asymptomatic patients, using chest radiographs, bone scans, and computed tomography (CT) scans, is not cost-effective.

[edit] Locally Advanced Disease (Stage III)

The term locally advanced breast cancer (LABC) has been applied to a heterogenous group of large tumors with extensive regional lymph node metastases and involvement of the skin or chest wall. This group composes 10% to 15% of breast cancer patients in the United States. The majority of patients with LABC will eventually develop distant metastases and thus have a uniformly poor prognosis.

Current management of LABC includes so-called neoadjuvant or induction chemotherapy before definitive local treatment of the primary lesion with surgery or radiation. This strategy improves both local and distant control, with more than 90% of patients rendered free of all gross disease. Dose-intense postoperative adjuvant regimens of chemotherapy with peripheral blood stem cell support are currently under investigation, particularly for women found to harbor large numbers of metastatic lymph nodes at surgery. Combined-modality therapy appears to have substantially improved survival of patients with LABC, with up to 50% of patients currently surviving for 5 years or more.

Inflammatory breast carcinoma (IBC) is often distinguished from other forms of LABC because of its aggressive natural history, with almost uniform mortality within 2 years due to the rapid development of disseminated disease. Clinical diagnosis is based on diffuse enlargement of the breast with erythema and induration or peau d'orange appearance of the skin. Because there is often no discrete underlying mass, this entity is often confused with acute mastitis. The latter, however, rarely occurs in nonlactating women. Involvement of dermal lymphatics with tumor emboli is the pathologic hallmark of IBC. The treatment strategy for IBC is similar to that for other forms of LABC.

[edit] Recurrent Disease

[edit] Local.

Locoregional recurrence after mastectomy often heralds systemic disease. For an isolated chest wall recurrence, complete surgical resection followed by radiotherapy is the treatment of choice. Local therapy may be all that is warranted, particularly if the time between primary therapy and recurrence (disease-free interval, DFI) is prolonged. Radiotherapy is indicated for the palliation of localized pain from inoperable metastases to the chest wall, axilla, or brachial plexus. HRT and chemotherapy can be effective in controlling local disease that is not amenable to surgery and radiation or that occurs coincident with systemic disease. In addition to local therapy, most patients eventually require systemic therapy, because they develop distant metastases that lead ultimately to death.

A recurrence within the breast after lumpectomy and radiation therapy does not confer the same dire prognosis as recurrence after mastectomy. Salvage mastectomy leads to prolonged survival in more than 50% of patients.

[edit] Metastatic.

Most patients with metastatic breast cancer (MBC) present with specific symptoms related to organ damage. MBC is a diverse disease. Its course ranges from indolent progression with a high quality of life to rapidly disabling symptoms that result in early death. From 20% to 30% of patients with MBC survive for 5 years, and up to 10% of patients survive for more than 10 years. The median survival is 2 to 3 years.

In general, MBC is highly treatable but rarely curable. Although most patients are responsive to initial systemic therapy, only a minority achieve complete remission (i.e., resolution of all evidence of disease). The primary goal of systemic therapy is the relief of symptoms and improvement or maintenance of a high quality of life. In many patients, even a toxic regimen that is effective in inducing tumor shrinkage is more likely to improve quality of life than a less toxic treatment with a low likelihood of response.

The success of MBC treatment depends on three main variables: tumor burden, tumor responsiveness to treatment, and patient performance status. Therefore patients should first undergo a staging workup to determine disease extent. Treatment is administered for a given period, usually 2 to 4 months, followed by restaging to assess response. A decision is then made whether to continue with the same therapy, change to a different therapy, or discontinue therapy altogether.

[edit] Staging and Treatment.

Breast cancers can metastasize to virtually any organ, leading to a variety of symptoms and complications. At autopsy, 50% to 70% of patients who die of breast cancer have widespread disease to lung, liver, and bone. Once MBC has been documented, a staging workup is performed to determine the sites and extent of metastases. Staging typically includes laboratory evaluation (CBC, liver enzymes, calcium, tumor markers such as carcinoembryonic antigen [CEA] and CA15-3), CT scans of the chest and abdomen, and a radionuclide bone scan. Documentation of MBC extent not only helps determine prognosis and the most appropriate approach to therapy, but also provides an objective way to measure the response to therapy.

The selection of systemic therapy is determined by MBC sites, hormone receptor status of tumor, patient age, and DFI. In general, patients with disease confined to soft tissue or bone are more likely to respond to endocrine therapy and survive longer than those with visceral disease. Patients with metastases involving the liver or with lymphangitic spread to the lungs are poor candidates for endocrine therapy and should be offered chemotherapy. In addition, patients with ER-positive or PR-positive tumors have a better prognosis, and more than 60% respond to hormonal manipulation. Patients with a DFI longer than 2 years have a significantly longer survival and a higher probability of responding to endocrine therapy than those with a shorter DFI.

[edit] Endocrine Therapy.

Pharmacologic doses of estrogens, antiestrogens, progestins, androgens, or corticosteroids, as well as pituitary, adrenal, and ovarian blockade, have been used to treat MBC with nearly equivalent response rates. Tamoxifen is currently the hormonal treatment of choice because of its low toxicity profile (see Table 43-7). Approximately two thirds of hormone receptor–positive patients respond to tamoxifen therapy. Up to half of hormone-sensitive patients who eventually fail tamoxifen therapy subsequently respond to second-line endocrine therapy. Two novel nonsteroidal inhibitors of aromatase, the enzyme that catalyzes the final step in the biosynthesis of estradiol and estrone outside the ovary, anastrozole and letrozole, are currently the drugs of choice in this setting because of their favorable toxicity profile. Alternatively, megestrol (Megace) a progestational agent, is often used in the United States. Its principal toxicity, which occurs in 20% to 50% of patients, is weight gain due to appetite stimulation. Fluid retention may be prohibitive in patients with cardiac dysfunction. Androgens, high doses of estrogens, and corticosteroids are rarely used because of undue toxicity.

Five percent to 10% of patients who embark on endocrine therapy experience a tumor flare, a transient worsening of pain at sites of bone metastases, within hours to weeks of treatment onset. Hypercalcemia may be induced or may worsen during this period but usually can be managed with supportive care without discontinuing treatment.

[edit] Chemotherapy.

Chemotherapy results in an objective (measurable) response in approximately two thirds of patients with MBC. Complete remission, however, is observed in only about 20%, and the median duration of response is about 1 year. Objective response rates to secondary regimens are 20% to 35%. The median survival after initiation of chemotherapy is approximately 3 years, but some patients may survive as long as 10 years. Chemotherapy is indicated for symptomatic relief for patients who are not good candidates for endocrine therapy. This group includes patients who have failed to respond to hormonal manipulation, are ER negative, have had a short DFI, or have liver lesions or lymphangitic spread to the lungs.

Combinations of cyclophosphamide and fluorouracil with either methotrexate (CMF) or doxorubicin (CAF) are often used as the primary regimens for most patients. The taxanes, which include paclitaxel (Taxol) and docetaxel (Taxotere), are highly active drugs for breast cancer and are often used as single agents, as is doxorubicin. The most active second-line regimens include other alkylating agents (e.g., thiotepa, melphalan), vinorelbine, 5-fluorouracil as prolonged infusion (or the oral equivalent, capecitabine), and mitomycin C. The most frequent toxicities observed with these chemotherapeutic agents are myelosuppression, nausea, vomiting, mucositis, and alopecia (see Table 43-7). Toxicities specific to individual agents include cardiotoxicity (doxorubicin), hemorrhagic cystitis (cyclophosphamide), neuropathy (paclitaxel), capillary leak syndrome (docetaxel), diarrhea (5-fluorouracil, capecitabine), ileus (vinorelbine), and pulmonary toxicity or hemolytic uremic syndrome (mitomycin C).

An exciting new agent for MBC treatment, Herceptin, is a humanized monoclonal antibody directed at the HER2/neu/erbB2 growth factor receptor. This relatively nontoxic agent dramatically potentiates the efficacy of cytotoxic agents such as paclitaxel in patients whose breast cancers overexpress HER2.

Unlike hormonal agents administered continuously for as long as response persists, there is probably no advantage to continuing the administration of chemotherapy beyond the time necessary to induce the best possible response (usually, approximately 6 months). Patients may then be followed off therapy until symptomatic progression occurs.

[edit] High-dose Therapy.

In recent years the focus of clinical research for MBC has shifted from palliation to cure for selected patients. Early findings indicate that high-dose chemotherapy followed by autologous bone marrow transplant or peripheral blood stem cell support may improve both disease-free survival and overall survival of MBC patients. The best candidates for this approach appear to be patients previously untreated for metastatic disease who have chemosensitive disease, with minimal residual tumor burden after induction chemotherapy. In early clinical trials, 15% to 20% of patients have remained free of disease off therapy for up to 3½ years. Longer follow-up is needed to determine how long these patients will remain in remission. Attempts to prolong these remissions by using antitumor vaccines or other biologic agents (e.g., Herceptin) are under investigation.

[edit] Specific Metastatic Sites.

The most common initial site of metastasis in breast cancer is bone. Radionuclide bone scanning is the most sensitive method for diagnosing skeletal metastases. Bone metastases can cause significant morbidity because of pain, pathologic fractures with resultant loss of function, and hypercalcemia. Expansion of vertebral metastases is the most common route of entry into the epidural space, leading to spinal cord compression with resultant paralysis. Abnormalities in weight-bearing bones should be further evaluated to rule out impending fractures that may require prophylactic orthopedic intervention. Monthly intravenous administration of a biphosphonate, such as pamidronate, significantly reduces the incidence of pathologic fractures and the need for radiation therapy to skeletal metastases for pain control.

Besides the bony skeleton, the lungs and pleurae are the most common sites of MBC. The major manifestations of pulmonary metastases include dry, irrepressible cough and dyspnea, whether from parenchymal disease, endobronchial metastases, or malignant pleural effusions. Although systemic therapy is indicated, highly symptomatic patients may require interventions that provide more rapid palliation. Chest tube drainage of large pleural effusions followed by pleurodesis produces symptomatic responses lasting longer than 1 month in 80% to 90% of patients. Endobronchial lesions that cause proximal airway obstruction can be effectively treated with laser ablation in most patients. High-dose corticosteroids may provide symptomatic relief of dyspnea in patients with lymphangitic carcinomatosis refractory to chemotherapy.

The incidence of clinically manifest brain metastases is approximately 10%. Presenting symptoms include headaches, behavioral changes, seizures, and focal neurologic deficits. After diagnosis with CT or MRI scans, symptomatic brain metastases are treated with high-dose dexamethasone and whole-brain irradiation. Surgery should be considered for the minority of patients with solitary metastases and well-controlled systemic disease. Patients who are able to undergo resection of solitary brain metastases followed by radiotherapy have a prolonged survival and better functional status than those who undergo radiotherapy alone.

Leptomeningeal metastasis (carcinomatous meningitis) presents with cranial nerve palsies and spinal or nerve root symptoms, along with the less specific findings of headache, nausea, vomiting, and mental status changes. Diagnosis is made by cytologic evaluation of the cerebrospinal fluid, although meningeal enhancement on gadolinium-enhanced MRI scans is highly suggestive. Localized irradiation may be administered for symptomatic cranial nerve palsies or other focal findings, followed by treatment with intrathecal chemotherapy. Although the majority of patients improve with therapy, fewer than 10% of patients survive for more than 1 year.

Breast cancer is the most common cause of epidural spinal cord compression. Rapid diagnosis and treatment are crucial to prevent permanent paralysis and sphincter dysfunction. Progressive back pain is the heralding symptom and is often accompanied by radicular pain. Signs of myelopathy, weakness, and sensory loss ensue and may progress rapidly. Total-spine MRI scans have supplanted myelography for rapid diagnosis and should be obtained at the first suspicion of cord compression. High doses of dexamethasone should be instituted immediately on diagnosis, followed by spinal irradiation. Most patients experience pain relief with treatment, but impaired ambulation or sphincter function is often irreversible and depends on the time of cord compromise. Neurosurgical intervention should be considered for rapidly progressive neurologic dysfunction despite radiation therapy.

[edit] PREVENTION OF BREAST CANCER

After the discovery of cytotoxic and endocrine agents active against breast cancer in the 1940s and 1950s, clinical research focused primarily on MBC treatment (Fig. 43-4). In the early 1970s, investigations focused on adjuvant systemic therapy, which successfully treats many women and significantly decreases overall breast cancer mortality. Results of the first large-scale intervention studies aimed at preventing the onset of breast cancer women at high risk have recently been reported. In the twenty-first century the main focus of research is likely to shift to primary prevention, affecting the lives of the estimated 29 million healthy women at increased risk. Primary care physicians must understand how to assess breast cancer risk in healthy women and how best to apply the available treatment modalities.

Figure 43-4 Treatment and prevention pyramid for women at risk for breast cancer, 1950-2010. MBC, Metastatic breast cancer.

[edit] Risk Factors

Although most women with breast cancer have no known genetic predisposition, definite risk factors for the development of breast cancer include genetic factors (family history, breast histopathology), hormonal factors (early menarche, late menopause, reproductive history, use of exogenous hormones), and environmental factors (high dietary fat intake, alcohol consumption, exposure to ionizing radiation). Table 43-8 summarizes the relative risks associated with various factors.

Table 43-8 Estimated Relative Risks of Developing Breast Cancer by Risk Factor

[edit] Family History.

A family history of breast cancer is among the strongest risk factors, particularly for women with first-degree relatives who have had breast cancer. The risk of developing breast cancer for patients with a second-degree relative who has had breast cancer is only slightly higher than the risk in the general population. A family history that includes both first-degree and second-degree relatives with breast cancer, however, particularly if the family members were diagnosed at a young age, constitutes strong evidence for autosomal dominant inheritance of a genetic predisposition for breast cancer. Such familial cases are more often bilateral and are often diagnosed at a younger age than sporadic cases. The inheritance of inactivating mutations in two genes, BRCA1 and BRCA2, may be directly involved in the development of most familial forms of breast cancer. Women who have inherited a mutant allele have an 80% lifetime risk of developing breast cancer, tenfold higher than women without the allele. Truly hereditary breast cancers constitute fewer than 5% of all cases.

[edit] Personal History.

Women with a past diagnosis of breast cancer are at high risk for the development of second primary breast cancer at an estimated rate of ½% to 1% per year. For example, a woman with early-stage breast cancer at age 30 and a remaining expected life span of 50 years has a 25% to 50% risk of developing a secondary cancer in either breast. As breast cancers are diagnosed earlier and their prognosis improves, the issue of preventing secondary primary cancers will become increasingly important.

[edit] Benign Breast Disease.

Epidemiologic analysis of benign (fibrocystic) breast disease has shown that nonproliferative lesions, including cysts, fibroadenoma, duct ectasia, fibrosis, and metaplasia, are not associated with an increased risk for breast cancer. Hyperproliferative epithelia without atypia, including ductal hyperplasia, sclerosing adenosis, and papilloma, are associated with a minimal increase in risk. Two histopathologic entities, atypical ductal hyperplasia and LCIS, are associated with a strong increase in risk for both the involved breast and the contralateral breast (approximately 0.2% per year), independent of family history (see Table 43-8).

[edit] Hormonal Factors.

Estrogens promote growth and development of breast cancer. Thus prolonged exposure of the breast epithelium to endogenous estrogens, as manifested by early menarche, late menopause, delayed childbearing, or postmenopausal obesity, increases breast cancer risk, whereas early menopause (without estrogen replacement) and multiple pregnancies have the opposite effect. The association between oral contraceptive use and breast cancer risk remains controversial. Prolonged use may mildly increase risk, but the risk level returns to baseline soon after the drug is discontinued. Moreover, most of the available data were derived from studies of women treated with higher doses of contraceptive estrogen than currently prescribed. Current evidence does not support the avoidance of oral contraceptive use (see Chapter 38 ). Postmenopausal HRT is extremely beneficial in terms of preventing bone loss and cardiovascular events. Beyond approximately 10 years, however, the risks of HRT in terms of promoting breast cancer development probably outweigh their beneficial effects on other organ systems (see Chapter 42 ).

[edit] Environmental Factors.

Exposure of the breast to therapeutic doses of ionizing radiation (typically about 40 Gy, e.g., in treatment of Hodgkin's disease), particularly during breast development (ages 10 to 19 years), dramatically increases cancer risk. Breast cancers become manifest after a lag period of approximately 15 years and with a frequency 10 to 75 times as high as in the general population. Thus 6-month clinical breast examinations and yearly mammograms are recommended for this group of women, beginning 10 to 15 years after the radiation exposure.

[edit] Risk Assessment Tools

A simple computerized interactive breast cancer risk assessment tool developed by Gail and others is distributed free by the NCI.✢✢The Breast Cancer Risk Assessment software can be ordered by calling 1-800-4-CANCER or by visiting NCI's cancer Trials Web site at http://cancertrials.nci.nih.gov.A computer algorithm is used to calculate an individual's 5-year or lifetime risk for the development of breast cancer, based on age at menarche, age at first live birth, history of breast cancer in first-degree relatives, and history of past breast biopsies, particularly if these revealed atypical ductal hyperplasia or LCIS. The Gail model is a useful and reliable tool in most patients but is poorly suited to identify women with hereditary breast cancer, who have a much higher lifetime risk. Thus the physician should obtain a detailed family history to identify women who are likely carriers of a BRCA1 or BRCA2 gene mutation. These include women with a first-degree relative with breast or ovarian cancer diagnosed under age 50 or those with multiple first-degree or second-degree relatives with breast cancer. These should then be referred for genetic counseling and testing.

[edit] Preventive Interventions

[edit] Prophylactic Mastectomy.

Prophylactic mastectomy is reserved for highly selected patients in a high-risk category. The indications for prophylactic mastectomy supported by the Society of Surgical Oncology include atypical hyperplasia of lobular or ductal origin, particularly if it is bilateral and multifocal; family history of premenopausal bilateral breast cancer in a mother or sister (family cancer syndrome); and fibronodular, dense breasts that are mammographically and clinically difficult to follow, coupled with either of the preceding problems.

[edit] Chemoprevention.

The high mortality rate of breast cancer despite advances in early diagnosis and treatment has prompted investigations into preventive measures using hormonal, dietary, and vitamin manipulations. Two nationwide clinical trials have been designed to study interventions that may reduce the incidence of breast cancers: the Breast Cancer Prevention Trial, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP P-1 trial), and the Women's Health Initiative (WHI), sponsored by the National Institutes of Health. The WHI is designed to test the overlapping effects of a low-fat diet, HRT, and calcium supplements on the incidence of cardiovascular disease, breast cancer, colon cancer, and osteoporosis. Results of this study will likely become available during the next decade.

The Breast Cancer Prevention Trial was designed to determine whether 5 years of therapy with tamoxifen can prevent breast cancer in women at increased risk. More than 13,000 women were enrolled in this trial. At a median follow-up of 69 months the incidence of new in situ and invasive breast cancers among women receiving tamoxifen was 50% lower than in the control group. In a second study of the same magnitude (P-2 or STAR trial) the preventive effect of tamoxifen will be compared to that of a novel estrogen receptor modulator, raloxifene, which may have a more favorable toxicity profile.

[edit] SPECIAL PATIENT POPULATIONS

[edit] Pregnant Patients

Gestational breast cancer complicates approximately 1:1000 pregnancies, accounting for about 3% of all breast cancers and 7% to 14% of breast cancers in women under age 40. Historically, breast cancer diagnosed during pregnancy was thought to carry a particularly poor prognosis. More recent studies, however, in which pregnant patients were compared with age-matched and stage-matched controls, have not demonstrated any difference in prognosis. Nonetheless, pregnant patients generally have more advanced disease at presentation, presumably from a delay in diagnosis of up to several months.

Modified radical mastectomy is the local treatment of choice for gestational breast cancer unless the pregnancy is terminated or the diagnosis is made close to delivery, because the radiotherapy necessary for breast preservation is contraindicated during pregnancy.

Pregnancy after treatment for breast cancer has not been associated with increased risk of recurrence. Patients should be counseled, however, that the risk of breast cancer recurrence continues for several years after the primary diagnosis, and family planning decisions should be made accordingly.

[edit] Patients Receiving Hormonal Replacement Therapy

HRT decreases the morbidity and mortality associated with cardiovascular disease and osteoporosis in postmenopausal women. Because premature menopause is a common side effect of adjuvant therapy for early-stage breast cancer, many young women face the risks of premature heart and bone disease and other conditions related to estrogen deficiency. Although the addition of progestins to estrogen protects against the development of estrogen-dependent endometrial carcinomas, the safety of HRT with respect to breast cancer has not been established. Therefore HRT is not advised for patients with a history of breast cancer. Adjuvant therapy with tamoxifen, however, has been shown to decrease bone loss because of its estrogen agonist effect on osteoclasts.

[edit] Elderly Patients

Breast cancer in elderly persons generally follows a more indolent course, often presenting as a well-circumscribed mass in this unscreened population. Mammography is helpful in estimating the amount of breast involvement and thus in planning treatment. Lumpectomy followed by tamoxifen alone can be substituted for more aggressive forms of treatment, particularly when extreme old age or other medical illnesses complicate the use of conventional therapy.

[edit] Male Patients

Approximately 1000 men are diagnosed with breast cancer in the United States every year, resulting in about 300 deaths a year. The mean age of men diagnosed with breast cancer is 60 to 70 years, approximately a decade older than that of women with breast cancer. Risk factors are similar to those in women: family history, exposure to radiation, high endogenous estrogen levels (secondary to liver disease or Klinefelter's syndrome), or exposure to exogenous estrogens. Stage for stage, survival rates are similar for men and women.

Management of male breast cancer parallels that for female breast cancer. Local treatment generally consists of mastectomy, followed by radiotherapy for LABC. The efficacy of adjuvant chemotherapy or tamoxifen for node- positive cancer in men has not been evaluated in randomized trials because of the small number of patients, but retrospective studies indicate that it is similar to that in women.

[edit] ADDITIONAL READINGS

• American Cancer Society: Cancer facts and figures, 2000 Atlanta: American Cancer Society; 2000:
• EB Claus, N Risch, WD Thompson: Autosomal dominant inheritance of breast cancer. Cancer 1994; 73:643.
• Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451.
• Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352:930.
• B Fisher, JP Costantino, DL Wickerham,et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371.
• JR Harris, ME Lippman, M Morrow, S Hellman: Diseases of the breast New York: Lippincott-Raven; 1996:
• PA Wingo, LA Ries, HM Rosenberg,et al.: Cancer incidence and mortality, 1973-1995: a report card for the U.S.. Cancer 1998; 82:1197.